Effect of ocean acidification on iron availability to marine phytoplankton.
The acidification caused by the dissolution of anthropogenic carbon dioxide (CO2) in the ocean changes the chemistry and hence the bioavailability of iron (Fe), a limiting nutrient in large oceanic regions. Here, we show that the bioavailability of dissolved Fe may decline because of ocean acidification. Acidification of media containing various Fe compounds decreases the Fe uptake rate of diatoms and coccolithophores to an extent predicted by the changes in Fe chemistry. A slower Fe uptake by a model diatom with decreasing pH is also seen in experiments with Atlantic surface water. The Fe requirement of model phytoplankton remains unchanged with increasing CO2. The ongoing acidification of seawater is likely to increase the Fe stress of phytoplankton populations in some areas of the ocean.


Autoantibodies in IDDM primarily recognize the 65,000-M(r) rather than the 67,000-M(r) isoform of glutamic acid decarboxylase.
Glutamic acid decarboxylase autoantibodies may aid in rapid screening strategies predicting IDDM before clinical onset. Rat islets contain GAD65 and GAD67 autoantibody targets, but human islets express only GAD65, now confirmed by direct immunoprecipitation from radiolabeled rat and human islets. Because human IDDM involves beta-cell-specific autoimmunity, we tested 190 new IDDM patients and 51 healthy control subjects for antibodies to recombinant human islet GAD65, rat islet GAD67, or human insulinoma/cerebellum GAD67, each expressed separately in hamster fibroblasts. By using immunoprecipitation, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and densitometric fluorogram scanning, 132 of 190 (70%) of new IDDM patients had GAD65 autoantibodies, whereas only 17 of 190 (9%) had antibodies to rat GAD67 (P < 0.001). Of healthy control subjects, 2 of 51 (3.9%) and 1 of 51 (1.9%) had antibodies to GAD65 and GAD67, respectively. All 17 GAD67 antibody-positive patients also had GAD65 antibodies; 14 of 17 with greater GAD65 than GAD67 index. Control studies showed comparable reactivity between recombinant rat and human GAD67 and between different subcellular preparations of recombinant GAD67 of either species. In conclusion, only GAD65 is expressed in human islets, the autoantibody response is primarily to this isoform, and GAD67 antibodies add little to IDDM detection.


Bilateral inferior petrosal sinus sampling: experience in 327 patients.
To describe findings and outcomes of 331 bilateral inferior petrosal sinus sampling (BIPSS) procedures performed in 327 patients evaluated for Cushing disease (CD). The radiology department's electronic database was searched to identify all BIPSS procedures (1990-2013). Electronic medical records were used to identify demographics, laboratory, procedural, surgical and pathologic findings. A total of 331 BIPSS procedures were performed in 327 patients (254 F, 73 M), mean age 41 (range 7-81) years. The overall technical success rate was 88% for bilateral cannulation, though nearly two-thirds of the technical failures had unilateral sampling that diagnosed CD. Of the 331 BIPSS procedures, 40 were performed without, and 291 with stimulation by Acthrel or desmopressin. Sensitivity was 89-94% for unstimulated BIPSS, 96% for stimulated BIPSS, and 77% for MRI. BIPSS lateralization was accurate in about half of patients, compared with 75% accuracy for MRI. Mean inferior petrosal sinus (IPS):peripheral adrenocorticotropic hormone ratio was 17.3 (SE 1.8) at baseline, and 99.2 (SE 14.8) at 3 min, with decreasing values over time. All patients with follow-up after surgical resection for centralizing BIPSS were reported to be cured, with cortisol levels significantly decreased from 19 to 4 μg/dL (p<0.0001). Complications from BIPSS were rare, including groin hematoma (2.5%), but no thromboembolic complications were seen. BIPSS remains the 'gold standard' for diagnosing CD. Stimulation with Acthrel or desmopressin is key to increasing specificity. When only one IPS can be successfully cannulated, results may still be diagnostic. BIPSS findings cannot be used to accurately lateralize lesions within the pituitary.


Gestational malaria: assessment of its consequences on fetal growth.
In a region of Africa (Nord-Kivu, Zaire) where malaria is endemic, circulating malaria parasites, malaria-associated placental lesions, and a low hemoglobin level (< 10 g/dl) were observed, either singly or in combination, in 73.1% of women (n = 461) delivering at the maternity hospital. These pathologic findings were associated with low birthweight in 18.1% of the newborns, whereas the prevalence of low birthweight was 6.4% among cases without these findings (P < 0.05). Parasitemia was observed in 17.4% of all mothers and was associated with a significant decrease in birthweight. Malaria-associated lesions were found in 52.5% of all placentas and were associated with a decrease in birthweight, head circumference, and ponderal index of the newborns. Such lesions were more frequently observed among primiparae (60.5%) than among multiparae (49.5%; P < 0.05). Lastly, a low hemoglobin level, found in 38.6% of the mothers, was associated with a decrease in birthweight, length, and head circumference. The differences in the physical effects associated with each of the pathologic conditions suggest that parasitemia, placental lesions, and anemia result in acute, subacute, and chronic impairment of fetal growth, respectively. Moreover, their deleterious effects may be cumulative, since the most dramatically affected physical patterns were found when the pathologic findings were associated in the same patient. Frequent antenatal monitoring of maternal hemoglobin and parasitemia, accompanied, when necessary, with curative treatments, may help to reduce the prevalence of intrauterine growth retardation and its procession of perinatal complications.


Ion Current-Based Proteomic Profiling for Understanding the Inhibitory Effect of Tumor Necrosis Factor Alpha on Myogenic Differentiation.
Despite a demonstrated role for TNF-α in promoting muscle wasting and cachexia, the associated molecular mechanisms and signaling pathways of myoblast differentiation dysregulated by TNF-α remain poorly understood. This study presents well-controlled proteomic profiling as a means to investigate the mechanisms of TNF-α-regulated myogenic differentiation. Primary human muscle precursor cells (MPCs) cultured in growth medium (GM), differentiation medium (DM) to induce myogenic differentiation, and DM with 20 ng/mL of TNF-α (n = 5/group) were comparatively analyzed by an ion current-based quantitative platform consisting of reproducible sample preparation/on-pellet digestion, a long-column nano-LC separation, and ion current-based differential analysis. The inhibition of myogenic differentiation by TNF-α was confirmed by reduced formation of multinucleated myotubes and the recovered expression of altered myogenic proteins such as MYOD and myogenin during myogenic differentiation. Functional analysis and validation by immunoassay analysis suggested that the cooperation of NF-κB and STAT proteins is responsible for dysregulated differentiation in MPCs by TNF-α treatment. Increased MHC class I components such as HLA-A, HLA-B, HLA-C, and beta-2-microglobulin were also observed in cultures in DM treated with TNF-α. Interestingly, inhibition of the cholesterol biosynthesis pathway during myogenic differentiation induced by serum starvation was not recovered by TNF-α treatment, which combined with previous reports, implies that this process may be an early event of myogenesis. This finding could lay the foundation for the potential use of statins in modulating myogenesis through cholesterol, for example, in stem cell-based myocardial infarction treatment, where differentiation of myoblasts and stem cells into force-generating mature muscle cells is a key step to the therapeutic capacity. In conclusion, the landscapes of altered transcription regulators, metabolic processes, and signaling pathways in MPCs are revealed in the regulation of myogenic differentiation by TNF-α, which is valuable for myogenic cellular therapeutics.


Dominance of Gas-Eating, Biofilm-Forming Methylobacterium Species in the Evaporator Cores of Automobile Air-Conditioning Systems.
Microbial communities in the evaporator core (EC) of automobile air-conditioning systems have a large impact on indoor air quality, such as malodor and allergenicity. DNA-based microbial population analysis of the ECs collected from South Korea, China, the United States, India, and the United Arab Emirates revealed the extraordinary dominance of Methylobacterium species in EC biofilms. Mixed-volatile organic compound (VOC) utilization and biofilm-forming capabilities were evaluated to explain the dominance of Methylobacterium species in the ECs. The superior growth of all Methylobacterium species could be possible under mixed-VOC conditions. Interestingly, two lifestyle groups of Methylobacterium species could be categorized as the aggregator group, which sticks together but forms a small amount of biofilm, and the biofilm-forming group, which forms a large amount of biofilm, and their genomes along with phenotypic assays were analyzed. Pili are some of the major contributors to the aggregator lifestyle, and succinoglycan exopolysaccharide production may be responsible for the biofilm formation. However, the coexistence of these two lifestyle Methylobacterium groups enhanced their biofilm formation compared to that with each single culture.IMPORTANCE Air-conditioning systems (ACS) are indispensable for human daily life; however, microbial community analysis in automobile ACS has yet to be comprehensively investigated. A bacterial community analysis of 24 heat exchanger fins from five countries (South Korea, China, the United States, India, and the United Arab Emirates [UAE]) revealed that Methylobacterium species are some of the dominant bacteria in automobile ACS. Furthermore, we suggested that the predominance of Methylobacterium species in automobile ACS is due to the utilization of mixed volatile organic compounds and their great ability for aggregation and biofilm formation.


Permeability of vaginal mucosa to water at normal and elevated temperatures.
A number of studies have clearly demonstrated that human vaginal mucosa may be used as a model of buccal mucosa for a variety of in vitro permeability studies on drugs and other chemical compounds. Furthermore, at between 25 degrees and 37 degrees C, a linear temperature-dependence of water flux across this mucosa, which was attributed to an increased fluidity of the principal lipoidal permeability barrier, was found to exist. The objective of the present study was to examine the behaviour of the above barrier on water fluxes at normal and elevated temperatures. Clinically healthy human vaginal mucosa specimens were obtained from excess tissue removed during a vaginal hysterectomy from a single patient, snap-frozen in liquid nitrogen and stored for 6 months at -85 degrees C. Seven sections from the mucosa were thawed in phosphate-buffered saline (PBS) and mounted in flow-through diffusion cells (exposed area 0.039 cm2). Their permeability to tritiated water was determined using a continuous flow-through perfusion system at temperatures of 37 degrees, 39 degrees and 41 degrees C. Three permeability experiments were performed at each temperature setting. Specimens were subjected to histological examination before and after permeability experiments. Mean water flux rates at steady state (10-24 h) were found to be 2,356 +/- 71 SEM, 3,020 +/- 38 SEM and 3,659 +/- 116 SEM cpm. cm-2.min-1, at temperatures of 37 degrees, 39 degrees and 41 degrees C, respectively. A linear regression analysis and plot (r2 = 0.99) displayed a slope of 325 +/- 4 SEM cpm.cm-2.min-1/degree C. The results of this study showed that, notwithstanding cellular damage, the principal physical permeability barrier was linearly temperature-dependent between the temperatures studied, providing further support for the concept that this barrier is lipoidal in nature.


Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.
A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.


Implementation of a structured hospital-wide morbidity and mortality rounds model.
There is a paucity of literature on the quality and effectiveness of institutional morbidity & mortality (M&M) rounds processes. We sought to implement and evaluate the effectiveness of a hospital-wide structured M&M rounds model at improving the quality of M&M rounds across multiple specialties. We conducted a prospective interventional study involving 24 clinical groups (1584 physicians) at a tertiary care teaching hospital from January 2013 to June 2015. We implemented the published Ottowa M&M Model (OM3): appropriate case selection, cognitive/system issues analyses, interprofessional participation, dissemination of lessons and effector mechanisms. We created an OM3 scoring index reflecting these elements to measure the quality of M&M rounds. Secondary outcomes include explicit discussions of cognitive/system issues and resultant action items. OM3 scores for all participating groups improved significantly from a median of 12.0/24 (95% CI 10 to 14) to 20.0/24 (95% CI 18 to 21). An increased frequency of in-rounds discussion around cognitive biases (pre 154/417 (37%), post 256/466 (55%); p<0.05) and system issues (pre 175/417 (42%), post 259/466 (62%); p<0.05) were reported by participants via online surveys postintervention, while in-person surveys throughout the intervention period demonstrated even higher frequencies (cognitive biases 1222/1437 (85%); system issues 1250/1437 (87%)). We found 45 action items resulting directly from M&M rounds postintervention, compared with none preintervention. Implementation of a structured model enhanced the quality of M&M rounds with demonstrable policy improvements hospital wide. The OM3 can be feasibly implemented at other hospitals to effectively improve quality of M&M rounds across different specialties.


Insulin release: the receptor hypothesis.
It is currently believed that the stimulation of insulin release by nutrient secretagogues reflects their capacity to act as fuel in pancreatic islet beta cells. In this review, it is proposed that such a fuel concept is not incompatible with a receptor hypothesis postulating the participation of cell-surface receptors in the recognition of selected nutrients as insulinotropic agents. Pursuant to this, attention is drawn to such matters as the anomeric specificity of the beta cell secretory response to D-glucose and its perturbation in diabetes mellitus, the insulinotropic action of artificial sweeteners, the possible role of bitter taste receptors in the stimulation of insulin secretion by L-glucose pentaacetate, the recently documented presence of cell-surface sweet taste receptors in insulin-producing cells, the multimodal signalling process resulting from the activation of these latter receptors, and the presence in beta cells of a sweet taste receptor mediating the fructose-induced potentiation of glucose-stimulated insulin secretion.


Plasmonic antiresonance through subwavelength hole arrays.
It has been shown both experimentally and numerically that the phenomenon of extraordinary transmission through subwavelength hole arrays is generally associated with a drop in transmission located very close to it. Paradoxically, this antiresonant drop occurs at the wavelength that, at first glance, should provoke a resonant excitation of a surface plasmon propagating along the metallic surface of the screen. The present paper gives a theoretical demonstration of this phenomenon, which dispels the paradox. Our theory is supported by numerical calculations.


Soluble receptor for advanced glycation end products alleviates nephritis in (NZB/NZW)F1 mice.
To investigate the efficacy of different doses of the soluble form of the receptor for advanced glycation end products (sRAGE) (conjugated to the Fc portion of immunoglobulin) in the treatment of nephritis in lupus-prone mice, in comparison with the efficacy of combination therapy with mycophenolate mofetil plus prednisolone. Twenty-eight female (NZB/NZW)F1 mice were divided into 5 groups (untreated, sRAGE [dose groups of 0.5, 1, or 2 μg], or mycophenolate mofetil plus prednisolone). Proteinuria and histologic damage were evaluated. Immune complex deposition and the nuclear translocation of NF-κB in the kidney tissue were assessed by immunofluorescence staining. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and IgG subclasses were also measured. The population of T cells was evaluated using a fluorescence-activated cell sorter, and expression of intracellular adhesion molecule 1 and vascular cell adhesion molecule 1 in the kidney tissue was assessed by immunohistochemical staining. In comparison with untreated mice, mice treated with 1 or 2 μg sRAGE showed significantly reduced proteinuria and attenuated histologic renal damage, with efficacy comparable to that of combination therapy. Treatment with 2 μg sRAGE significantly reduced immune complex deposition and decreased the serum concentrations of anti-dsDNA, IgG2a, IgG2b, and IgG3. In addition, sRAGE interrupted the nuclear translocation of NF-κB in the kidney, resulting in reduction in the expression of downstream genes of NF-κB in vivo and in vitro. Furthermore, sRAGE effectively modified T cell populations. Treatment with sRAGE significantly improved nephritis in lupus-prone mice, with efficacy comparable to that of standard induction treatment for lupus nephritis. These data suggest that sRAGE has antiinflammatory effects on the pathophysiology of lupus nephritis and could serve as a potent new therapy for this disease.


A cluster of Vibrio cholerae O1 infections in French travelers to Rajasthan (India), May 2006.
A woman aged 60 years was hospitalized for Vibrio cholerae serogroup O1 cholera. Twenty-six fellow travelers and 48 health care workers who cared for the patient were individually traced and contacted. Of the 23/27 travelers with diarrhea during the trip, 4 presented antibodies. There was no person-to-person transmission.


Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity.
Nutrient availability varies seasonally and spatially in the wild. While many animals, such as hibernating animals or migrating birds, evolved strategies to overcome periods of nutrient scarcity,1,2 the cellular mechanisms of these strategies are poorly understood. Cave environments represent an example of nutrient-deprived environments, since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability.3 Here, we used Astyanax mexicanus, which includes river-dwelling surface fish and cave-adapted cavefish populations, to study the genetic adaptation to nutrient limitations.4-9 We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue.10-12 Moreover, the lipid metabolism regulator, peroxisome proliferator-activated receptor γ (Pparγ), is upregulated at both transcript and protein levels in cavefish livers. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that Pparγ binds cavefish promoter regions of genes to a higher extent than surface fish and inhibiting Pparγ in vivo decreases fat accumulation in A. mexicanus. Finally, we identified nonsense mutations in per2, a known repressor of Pparγ, providing a possible regulatory mechanism of Pparγ in cavefish. Taken together, our study reveals that upregulated Pparγ promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient-limited environments.


Is her-2 status in the primary tumor correlated with matched lymph node metastases in patients with gastric cancer undergoing curative gastrectomy?
HER2 expression in the primary tumor and its lymph node metastases vary in gastric cancer, reflecting intratumoral heterogeneity. This finding also suggests that proliferation of a different clone in metastatic nodes is possible. In the current study, we aimed to determine the cause of discordance in HER-2 expression in the primary tumor and lymph node metastases for patients with gastric cancer. Eighty-one patients with gastric cancer who had undergone radical gastrectomy and were found to have lymph node metastasis upon pathological examination were included. Histopathological samples were obtained from biopsies obtained during patient gastrectomies and lymph node dissection. HER2 status was evaluated by both immunohistochemistry (IHC) and silver in situ hybridization (SISH). Sixty-four (79%) patients were SISH (-), while 17 (21%) were SISH (+) in the primary tumor. However, in metastatic lymph nodes, HER2 status was SISH positive in 5 (28.3%) of the 64 SISH (-) primary tumor specimens. One of the 17 SISH (+) primary tumors was SISH (-) in the metastatic lymph nodes. Thus, SISH results for HER2 in both primary tumors and lymph node metastases were comparable, showing a concordance of 92.5%. In total, six patients demonstrated discordance between the primary tumor and lymph node metastases. The prevalence of HER2 discordance was significantly higher for patients in the pN2 and N3 stages (p=0.007). Although discordant patients had worse survival rates than concordant patients, the differences were not significant (p>0.05). Our study indicates that the frequency of concordance in HER2 status, as determined by IHC or SISH, is high in primary tumors and their corresponding lymph node metastases for patients with gastric cancer. If there is a discrepancy in HER2 status, its evaluation by both IHC and SISH may be useful for detecting patients who would benefit from trastuzumab, and it would therefore help guide decision-making processes in administering treatment.


Exploring the variation in paediatric tonsillectomy rates between English regions: a 5-year NHS and independent sector data analysis.
Tonsillectomy rates vary between locations and socio-economic groups and have been noted to do so since the 1930s. We aimed, first, to illustrate the current extent of variation in rates in the NHS across England and, second, to explore whether any observed geographical variation could be accounted for by combining independent sector data with standard NHS datasets. Analysis of NHS Hospital Episode Statistics data for tonsillectomy in people aged under 15 years, from April 1 2000 to March 31 2005; addition of data from a major independent sector provider of surgery; ranking of local authority areas according to tonsillectomy rates including and excluding independent sector data. The national annual average tonsillectomy rate for the NHS was 304 per 100 000 population aged <15 (95% CI 320-324). The highest rate was 754 (95% CI 690-822) and the lowest 102 (95% CI 83-125). This seven-fold difference cannot simply be explained by a small number of high or low 'outliers'. When rates in the NHS were ranked and compared with the ranking of rates in the independent sector data, a Kendall tau rank correlation coefficient of 0.003 showed that there was no inverse correlation between the two rankings. That is, low NHS rates were not associated with high independent sector rates or vice versa. There is currently a seven-fold variation in tonsillectomy rates across local authority areas in England. The variation in tonsillectomy rates found in NHS data on surgical workload does not appear to be explained by the exclusion of data from the independent sector.


Complex Structured Fluorescent Polythiophene Graft Copolymer as a Versatile Tool for Imaging, Targeted Delivery of Paclitaxel, and Radiotherapy.
Advances in polymer chemistry resulted in substantial interest to utilize their diverse intrinsic advantages for biomedical research. Especially, studies on drug delivery for tumors have increased to a great extent. In this study, a novel fluorescent graft copolymer has been modified by a drug and targeting moiety and the resulting structure has been characterized by alterations in fluorescent intensity. The polythiophene based hybrid graft copolymer was synthesized by successive organic reactions and combination of in situ N-carboxy anhydride (NCA) ring opening and Suzuki coupling polymerization processes. Initially, targeted delivery of the graft copolymer was investigated by introducing a tumor specific ligand, anti-HER2/neu antibody, on the structure. The functionalized polymer was able to differentially indicate HER2-expressing A549 human lung carcinoma cells, whereas no signal was obtained for Vero, monkey kidney epithelial cells, and HeLa, human cervix adenocarcinoma cells. After integrating paclitaxel into the structure, cell viability, cell cycle progression, and radiosensitivity studies demonstrate HER2/neu targeting polymers were most effective to inhibit cell proliferation. Importantly, the graft copolymer used had no cytotoxic effects to cells, as evidenced by cell viability and cell cycle analysis. This work clearly confirms that a specially designed and fabricated graft copolymer with a highly complex structure is a promising theranostic agent capable of targeting tumor cells for diagnostic and therapeutic purposes.


Identification and Functional Characterization of Glycosylation of Recombinant Human Platelet-Derived Growth Factor-BB in Pichia pastoris.
Yeast Pichia pastoris is a widely used system for heterologous protein expression. However, post-translational modifications, especially glycosylation, usually impede pharmaceutical application of recombinant proteins because of unexpected alterations in protein structure and function. The aim of this study was to identify glycosylation sites on recombinant human platelet-derived growth factor-BB (rhPDGF-BB) secreted by P. pastoris, and investigate possible effects of O-linked glycans on PDGF-BB functional activity. PDGF-BB secreted by P. pastoris is very heterogeneous and contains multiple isoforms. We demonstrated that PDGF-BB was O-glycosylated during the secretion process and detected putative O-glycosylation sites using glycosylation staining and immunoblotting. By site-directed mutagenesis and high-resolution LC/MS analysis, we, for the first time, identified two threonine residues at the C-terminus as the major O-glycosylation sites on rhPDGF-BB produced in P. pastoris. Although O-glycosylation resulted in heterogeneous protein expression, the removal of glycosylation sites did not affect rhPDGF-BB mitogenic activity. In addition, the unglycosylated PDGF-BBΔGly mutant exhibited the immunogenicity comparable to that of the wild-type form. Furthermore, antiserum against PDGF-BBΔGly also recognized glycosylated PDGF-BB, indicating that protein immunogenicity was unaltered by glycosylation. These findings elucidate the effect of glycosylation on PDGF-BB structure and biological activity, and can potentially contribute to the design and production of homogeneously expressed unglycosylated or human-type glycosylated PDGF-BB in P. pastoris for pharmaceutical applications.


Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer.
Triple-negative breast cancers contain a spectrum of epithelial and mesenchymal phenotypes. SUM-229PE cells represent a model for this heterogeneity, maintaining both epithelial and mesenchymal subpopulations that are genomically similar but distinct in gene expression profiles. We identified differential regions of open chromatin in epithelial and mesenchymal cells that were strongly correlated with regions of H3K27ac. Motif analysis of these regions identified consensus sequences for transcription factors that regulate cell identity. Treatment with the MEK inhibitor trametinib induced enhancer remodeling that is associated with transcriptional regulation of genes in epithelial and mesenchymal cells. Motif analysis of enhancer peaks downregulated in response to chronic treatment with trametinib identified AP-1 motif enrichment in both epithelial and mesenchymal subpopulations. Chromatin immunoprecipitation sequencing (ChIP-seq) of JUNB identified subpopulation-specific localization, which was significantly enriched at regions of open chromatin. These results indicate that cell identity controls localization of transcription factors and chromatin-modifying enzymes to enhancers for differential control of gene expression. We identified increased H3K27ac at an enhancer region proximal to CXCR7, a G-protein-coupled receptor that increased 15-fold in expression in the epithelial subpopulation during chronic treatment. RNAi knockdown of CXCR7 inhibited proliferation in trametinib-resistant cells. Thus, adaptive resistance to chronic trametinib treatment contributes to proliferation in the presence of the drug. Acquired amplification of KRAS following trametinib dose escalation further contributed to POS cell proliferation. Adaptive followed by acquired gene expression changes contributed to proliferation in trametinib-resistant cells, suggesting inhibition of early transcriptional reprogramming could prevent resistance and the bypass of targeted therapy. IMPLICATIONS: We defined the differential responses to trametinib in subpopulations of a clinically relevant in vitro model of TNBC, and identified both adaptive and acquired elements that contribute to the emergence of drug resistance mediated by increased expression of CXCR7 and amplification of KRAS.


Virulence Determinants Are Required for Brain Abscess Formation Through Staphylococcus aureus Infection and Are Potential Targets of Antivirulence Factor Therapy.
Bacterial brain abscesses (BAs) are difficult to treat with conventional antibiotics. Thus, the development of alternative therapeutic strategies for BAs is of high priority. Identifying the virulence determinants that contribute to BA formation induced by Staphylococcus aureus would improve the effectiveness of interventions for this disease. In this study, RT-qPCR was performed to compare the expression levels of 42 putative virulence determinants of S. aureus strains Newman and XQ during murine BA formation, ear colonization, and bacteremia. The alterations in the expression levels of 23 genes were further confirmed through specific TaqMan RT-qPCR. Eleven S. aureus genes that persistently upregulated expression levels during BA infection were identified, and their functions in BA formation were confirmed through isogenic mutant experiments. Bacterial loads and BA volumes in mice infected with isdA, isdC, lgt, hla, or spa deletion mutants and the hla/spa double mutant strain were lower than those in mice infected with the wild-type Newman strain. The therapeutic application of monoclonal antibodies against Hla and SpA decreased bacterial loads and BA volume in mice infected with Newman. This study provides insights into the virulence determinants that contribute to staphylococcal BA formation and a paradigm for antivirulence factor therapy against S. aureus infections.


Potentiation Following Ballistic and Nonballistic Complexes: The Effect of Strength Level.
Suchomel, TJ, Sato, K, DeWeese, BH, Ebben, WP, and Stone, MH. Potentiation following ballistic and nonballistic complexes: the effect of strength level. J Strength Cond Res 30(7): 1825-1833, 2016-The purpose of this study was to compare the temporal profile of strong and weak subjects during ballistic and nonballistic potentiation complexes. Eight strong (relative back squat = 2.1 ± 0.1 times body mass) and 8 weak (relative back squat = 1.6 ± 0.2 times body mass) males performed squat jumps immediately and every minute up to 10 minutes following potentiation complexes that included ballistic or nonballistic concentric-only half-squat (COHS) performed at 90% of their 1 repetition maximum COHS. Jump height (JH) and allometrically scaled peak power (PPa) were compared using a series of 2 × 12 repeated measures analyses of variance. No statistically significant strength level main effects for JH (p = 0.442) or PPa (p = 0.078) existed during the ballistic condition. In contrast, statistically significant main effects for time existed for both JH (p = 0.014) and PPa (p < 0.001); however, no statistically significant pairwise comparisons were present (p > 0.05). Statistically significant strength level main effects existed for PPa (p = 0.039) but not for JH (p = 0.137) during the nonballistic condition. Post hoc analysis revealed that the strong subjects produced statistically greater PPa than the weaker subjects (p = 0.039). Statistically significant time main effects existed for time existed for PPa (p = 0.015), but not for JH (p = 0.178). No statistically significant strength level × time interaction effects for JH (p = 0.319) or PPa (p = 0.203) were present for the ballistic or nonballistic conditions. Practical significance indicated by effect sizes and the relationships between maximum potentiation and relative strength suggest that stronger subjects potentiate earlier and to a greater extent than weaker subjects during ballistic and nonballistic potentiation complexes.


Short-term effects of a course of manual therapy and exercise in people with moderate chronic obstructive pulmonary disease: a preliminary clinical trial.
The purpose of this preliminary study was to demonstrate the feasibility of a study that measures the short-term effects of a course of manual therapy (MT) and exercise (Ex) in people with moderate chronic obstructive pulmonary disease (COPD). Fifteen participants (9 males; mean age, 56.1 years), with moderate COPD (mean % predicted forced expiratory volume in the first second [FEV1% predicted], 61.8%), were randomly allocated to 1 of 3 groups: soft tissue therapy only (ST); ST and spinal manipulation (SM); or ST, SM, and Ex. The intervention continued for 4 weeks. Outcome measures included FEV1, forced vital capacity (FVC), chronic respiratory questionnaire (CRQ-SAS) scores, distance walked in a 6-minute walking test, and monitoring for adverse events. There was an increase in FVC for the SM + ST + Ex group compared with ST only and ST + SM (1.01 and 1.00 L, respectively). Distance walked increased in the ST + SM and ST + SM + Ex groups compared with ST only (120.0 and 168.0 m, respectively). Dyspnea levels decreased in the ST + SM and ST + SM + Ex groups compared with ST only (0.64 and 0.44, respectively). There were no major or moderate adverse events reported following ST or SM interventions. For this small group of patients, combining MT with Ex produced short improvements in FVC, distance walked, and dyspnea levels, with no major or moderate adverse events. This preliminary study showed that a larger study evaluating the clinical outcomes of MT for people with moderate COPD appears feasible.


A hybrid position/force control approach for identification of deformation models of skin and underlying tissues.
In this paper, the focus is on the design of two biomechanical models representing the skin as well as the underlying tissues behavior and properties during a robotized harvesting process. The first model is quasi-static (i.e., without considering velocity) in the pressure direction of the tool: it is principally issued from the work of d'Aulignac et al. and some interesting properties are exhibited from it. The second model is new and takes into account velocity and lubrication in the motion direction of the tool. The goal of this study is to improve skin harvesting process in robotized reconstructive surgery, by automatically selecting the force applied on the donor area and tuning the gain factors of the control law prior to harvesting. It requires extracting relevant parameters such as skin thickness and stiffness, friction coefficient, etc. that characterize the biomechanical properties of the skin and underlying tissues of each patient and of different harvesting surfaces on a given patient (thigh, skull, buttocks, ...). Due to the surgical constraint, the in vivo procedure should be performed in the operating room before starting the operation with the robot itself thanks to a suitable hybrid position/force controller. In this paper, a survey about soft tissue modeling is presented. Mathematical models are discussed along with identification protocols, and two models are chosen that meet our requirements. Finally, experimental results are presented on foam and human skin.


Remission of anosognosia for right hemiplegia and neglect after caloric vestibular stimulation.
Neglect and related phenomena, as anosognosia for hemiplegia and somatoparaphrenia, are often associated to right-hemisphere lesions. These deficits can be alleviated by caloric vestibular stimulation, but little is known about the efficacy of this physiological intervention on neglect following left-hemisphere lesions. Here we report the case of an ambidextrous left brain-damaged patient with severe right personal and extrapersonal neglect, anosognosia for right hemiplegia and somatoparaphrenia. These symptoms co-occurred with more typical manifestations of left-brain damage, such as aphasia and apraxia. Neurological examination revealed right hemiplegia, hemianesthesia and hemianopia. Visuo-spatial tests for personal and extrapersonal neglect, as well as an anosognosia questionnaire, were submitted before and after caloric vestibular stimulation. Results showed a dramatic improvement of anosognosia for hemiplegia and neglect; no change was observed for the remaining deficits. The results confirm the notion of the selectivity of vestibular stimulation for neglect and related disorders and extend this notion by showing that similar effects can be obtained after lesion of the left hemisphere, suggesting that similar mechanisms are responsible for left- and right-sided neglect. Such a peculiar association of language and visuo-spatial disorders jointly present after a left-sided lesion opens the question of the link between handedness and lateralization of cognitive functions.


Efficacy of a single intravenous dose of amphotericin B for Candida urinary tract infections: further favorable experience.
Studies in experimental animals and humans have shown that Amphotericin B (AmB) persists in urine for days to weeks after a single IV dose in levels that should inhibit candidal organisms and thereby obviate the need for frequent dosing. Including data from four previously described patients, we have now treated a total of 11 patients (12 episodes) with Candida urinary tract infections with single-dose AmB (six, Candida albicans; two, C. tropicalis; four, other nonalbicans Candida). The duration of candiduria prior to entry ranged from 18 to 180 days. Predisposing conditions included renal transplantation (1), diabetes mellitus (8), genitourinary stones (1) or anomalies (4), catheterization (2), and antibacterial therapy (11). A single patient was intolerant of AmB. Out of 11 evaluable candiduric episodes, eight resolved. Failure occurred in one patient with a chronic indwelling bladder catheter and in the allograft recipient. The data suggest that the sustained urinary excretion of AmB may permit successful single- or paucidose therapy of Candida urinary tract infections in some patients with a minimum of toxicity.


Current management of biliary atresia.
Extra-hepatic biliary atresia occurs in approximately 1:15,000 live births leading to about 50 new cases/year in the UK. Presentation is with prolonged jaundice, usually in a term baby who develops signs of obstructive jaundice. Management has been improved by public and professional education to encourage early referral and diagnosis to facilitate initial surgery before 8 weeks of age. Surgical management is complementary and includes an attempt to restore biliary flow (the Kasai portoenterostomy) and liver transplantation if necessary. Medical management consists of antibiotics, ursodeoxycholic acid to encourage bile flow, fat soluble vitamin supplementation and nutritional support. Centralising surgery to specialised centres has improved survival of this potentially fatal disease to over 90% in the UK. Over half of infants undergoing portoenterostomy will clear the jaundice and have a greater than 80% chance of a good quality of life, reaching adolescence without transplantation. For those children developing intractable complications of cirrhosis and portal hypertension, liver transplantation provides a 90% chance of achieving normal life.


Weighted lasso in graphical Gaussian modeling for large gene network estimation based on microarray data.
We propose a statistical method based on graphical Gaussian models for estimating large gene networks from DNA microarray data. In estimating large gene networks, the number of genes is larger than the number of samples, we need to consider some restrictions for model building. We propose weighted lasso estimation for the graphical Gaussian models as a model of large gene networks. In the proposed method, the structural learning for gene networks is equivalent to the selection of the regularization parameters included in the weighted lasso estimation. We investigate this problem from a Bayes approach and derive an empirical Bayesian information criterion for choosing them. Unlike Bayesian network approach, our method can find the optimal network structure and does not require to use heuristic structural learning algorithm. We conduct Monte Carlo simulation to show the effectiveness of the proposed method. We also analyze Arabidopsis thaliana microarray data and estimate gene networks.


Pediatric Readiness in Emergency Medical Services Systems.
Ill and injured children have unique needs that can be magnified when the child's ailment is serious or life-threatening. This is especially true in the out-of-hospital environment. Providing high-quality out-of-hospital care to children requires an emergency medical services (EMS) system infrastructure designed to support the care of pediatric patients. As in the emergency department setting, it is important that all EMS agencies have the appropriate resources, including physician oversight, trained and competent staff, education, policies, medications, equipment, and supplies, to provide effective emergency care for children. Resource availability across EMS agencies is variable, making it essential that EMS medical directors, administrators, and personnel collaborate with outpatient and hospital-based pediatric experts, especially those in emergency departments, to optimize prehospital emergency care for children. The principles in the policy statement "Pediatric Readiness in Emergency Medical Services Systems" and this accompanying technical report establish a foundation on which to build optimal pediatric care within EMS systems and serve as a resource for clinical and administrative EMS leaders.


Optimal medical outcomes with limited liability: risk management principles for medical practices at the intersection of medicine, law, and business.
Physicians practice at the intersection of medicine, law, and business. Each discipline creates its own challenges for the practicing physician: to practice efficient, effective medicine; to limit potential liability; and to create a positive financial outcome. Those challenges increase with escalating costs and reduced reimbursements. In this paper, the common clinical presentation of chest pain has been used to create a paradigm to educate physicians to understand efficient and effective approaches to diagnosis and treatment, and how effective communication with patients and meticulous documentation of all medical encounters can limit the potential for liability. Ultimately, given today's reimbursement formulas, physicians must also understand the cost of testing, in relation to its benefits, in an attempt to yield a positive financial outcome.


Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP.
NMDA receptor (NMDAR)-mediated excitotoxicity plays an important role in several CNS disorders, including epilepsy, stroke, and ischemia. Here we demonstrate the involvement of striatal-enriched protein tyrosine phosphatase (STEP) in this critical process. STEP(61) is an alternatively spliced member of the family that is present in postsynaptic terminals. In an apparent paradox, STEP(61) regulates extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, two proteins with opposing functions; activated p38 promotes cell death, whereas activated ERK1/2 promotes cell survival. We found that synaptic stimulation of NMDARs promoted STEP(61) ubiquitination and degradation, concomitant with ERK1/2 activation. In contrast, extrasynaptic stimulation of NMDARs invoked calpain-mediated proteolysis of STEP(61), producing the truncated cleavage product STEP(33) and activation of p38. The calpain cleavage site on STEP was mapped to the kinase interacting motif, a domain required for substrate binding. As a result, STEP(33) neither interacts with nor dephosphorylates STEP substrates. A synthetic peptide spanning the calpain cleavage site efficiently reduced STEP(61) degradation and attenuated p38 activation and cell death in slice models. Furthermore, this peptide was neuroprotective when neurons were subjected to excitotoxicity or cortical slices were exposed to ischemic conditions. These findings suggest a novel mechanism by which differential NMDAR stimulation regulates STEP(61) to promote either ERK1/2 or p38 activation and identifies calpain cleavage of STEP(61) as a valid target for the development of neuroprotective therapy.


Intrathecal Contrast-Enhanced Magnetic Resonance Imaging-Related Brain Signal Changes: Residual Gadolinium Deposition?
There have been recent studies evaluating brain magnetic resonance imaging changes in patients with normal renal function, after intravenous administration of gadolinium-based contrast agents (GBCAs). Their findings were supported by histological evidence as well and brought a new vision concerning what needs to be learned to provide better patient care. In this report, we aim to present brain magnetic resonance imaging changes after intrathecal administration of a linear ionic agent (gadopentetate dimeglumine). We evaluated hyperintensities in the deep nuclei of the brain in 6 patients with normal renal function after intrathecal administration of a linear ionic GBCA, without other confounding intravenous GBCA administrations. For visual analysis, T1 signal hyperintensity of the globus pallidus (GP), putamen, pons, and dentate nucleus (DN) were scored on a 4-point scale. For quantitative analysis, using the unenhanced T1-weighted images oval regions of interests were placed within the DN, central pons, GP, and thalamus on different image slice positions. On visual analysis, 5 patients had T1 signal hyperintensity of the DN and GP, whereas the DN/pons signal intensity and the GP/thalamus signal intensity were found to be increased in all 6. This observation not only adds to our fund of knowledge concerning biodistribution and pharmacokinetics of those agents, but also raises the question of a possible association with the glymphatic pathway.


A Coordinated Multi-study Analysis of the Longitudinal Association Between Handgrip Strength and Cognitive Function in Older Adults.
Handgrip strength, an indicator of overall muscle strength, has been found to be associated with slower rate of cognitive decline and decreased risk for cognitive impairment and dementia. However, evaluating the replicability of associations between aging-related changes in physical and cognitive functioning is challenging due to differences in study designs and analytical models. A multiple-study coordinated analysis approach was used to generate new longitudinal results based on comparable construct-level measurements and identical statistical models and to facilitate replication and research synthesis. We performed coordinated analysis on 9 cohort studies affiliated with the Integrative Analysis of Longitudinal Studies of Aging and Dementia (IALSA) research network. Bivariate linear mixed models were used to examine associations among individual differences in baseline level, rate of change, and occasion-specific variation across grip strength and indicators of cognitive function, including mental status, processing speed, attention and working memory, perceptual reasoning, verbal ability, and learning and memory. Results were summarized using meta-analysis. After adjustment for covariates, we found an overall moderate association between change in grip strength and change in each cognitive domain for both males and females: Average correlation coefficient was 0.55 (95% CI = 0.44-0.56). We also found a high level of heterogeneity in this association across studies. Meta-analytic results from nine longitudinal studies showed consistently positive associations between linear rates of change in grip strength and changes in cognitive functioning. Future work will benefit from the examination of individual patterns of change to understand the heterogeneity in rates of aging and health-related changes across physical and cognitive biomarkers.


290 metagenome-assembled genomes from the Mediterranean Sea: a resource for marine microbiology.
The Tara Oceans Expedition has provided large, publicly-accessible microbial metagenomic datasets from a circumnavigation of the globe. Utilizing several size fractions from the samples originating in the Mediterranean Sea, we have used current assembly and binning techniques to reconstruct 290 putative draft metagenome-assembled bacterial and archaeal genomes, with an estimated completion of ≥50%, and an additional 2,786 bins, with estimated completion of 0-50%. We have submitted our results, including initial taxonomic and phylogenetic assignments, for the putative draft genomes to open-access repositories for the scientific community to use in ongoing research.


Cross talk between CD3 and CD28 is spatially modulated by protein lateral mobility.
Functional convergence of CD28 costimulation and TCR signaling is critical to T-cell activation and adaptive immunity. These receptors form complex microscale patterns within the immune synapse, although the impact of this spatial organization on cell signaling remains unclear. We investigate this cross talk using micropatterned surfaces that present ligands to these membrane proteins in order to control the organization of signaling molecules within the cell-substrate interface. While primary human CD4(+) T cells were activated by features containing ligands to both CD3 and CD28, this functional convergence was curtailed on surfaces in which engagement of these two systems was separated by micrometer-scale distances. Moreover, phosphorylated Lck was concentrated to regions of CD3 engagement and exhibited a low diffusion rate, suggesting that costimulation is controlled by a balance between the transport of active Lck to CD28 and its deactivation. In support of this model, disruption of the actin cytoskeleton increased Lck mobility and allowed functional T-cell costimulation by spatially separated CD3 and CD28. In primary mouse CD4(+) T cells, a complementary system, reducing the membrane mobility increased the sensitivity to CD3-CD28 separation. These results demonstrate a subcellular reaction-diffusion system that allows cells to sense the microscale organization of the extracellular environment.


Mechanism of Discrimination of 8-Oxoguanosine versus Guanosine by Escherichia coli Fpg.
The mutagenic 8-oxoguanosine monophosphate, the predominant product of DNA oxidation, is excised by formamidopyrimidine glycosylase (Fpg) in bacteria. The mechanism of recognition of 8-oxodG, which differs subtly from its normal counterpart, guanosine monophosphate (dG), by Escherichia coli Fpg remains elusive due to the lack of structural data of E. coli Fpg bound to 8-oxodG. Here, we present solution-state structure of 8-oxodG oligomer bound to E. coli E3Q Fpg using UV resonance Raman (UVRR) spectroscopy. The vibrational spectra report on the π-stacking and hydrogen bonding interactions established by 8-oxodG with E. coli E3Q Fpg. Furthermore, we report on the interactions of E. coli E3Q Fpg with the normal, undamaged nucleotide, dG. We show that E. coli Fpg recognizes 8-oxodG and dG through their C2-amino group but only 8-oxodG forms extensive contacts with E. coli Fpg. Our findings provide a basis for mechanism of lesion recognition by E. coli Fpg.


Identification of medically important yeasts by sequence analysis of the internal transcribed spacer and D1/D2 region of the large ribosomal subunit.
The prevalence of opportunistic yeast infections has increased in recent decades as the result of an increasing immunocompromised patient population. To evaluate ribosomal RNA (rRNA) gene sequence to identify medically important yeast species, to investigate the performance of both the rRNA gene internal transcribed spacer (ITS) and D1/D2 region in identifying clinically relevant yeasts, and to compare these results with those of a standard phenotypic method. Both regions from 50 yeast strains, comprising 45 clinical isolates and 5 reference strains, were amplified using PCR and then sequenced. The sequences were compared to reference data available from the GenBank database of the National Center for Biotechnology Information using the BLASTn tool. Using ID32C, 88% (44/50) of all strains were identified accurately at the species level, although 6% were misidentified; two Candida eremophila isolates were identified as Candida glabrata and Candida tropicalis, and one Saprochaete clavata isolate was identified as Saprochaete capitata. Two of the four isolates identified by phenotypic methods as Trichosporon asahii were defined so by analyzing the ITS region, but the remaining two were not distinguishable from closely related species. Based on the D1/D2 region, these four isolates had 100% sequence identity with T. asahii, Trichosporon japonicum, and Trichosporon asteroides. The isolate identified as Trichosporon inkin using ID32C could not be distinguished from Trichosporon ovoides by analyzing the ITS and D1/D2 regions. Identifying medically important yeasts by sequencing the ITS and D1/D2 region is a rapid and reliable alternative to conventional identification methods. For a diagnostic algorithm, we suggest a two-step procedure integrating conventional methods (e.g. microscopic morphology on corn meal agar with Tween® 80 and API ID32C®) and sequence analysis of the ITS and D1/D2 region.


Societal preferences for distributive justice in the allocation of health care resources: a latent class discrete choice experiment.
Economic theory suggests that resources should be allocated in a way that produces the greatest outputs, on the grounds that maximizing output allows for a redistribution that could benefit everyone. In health care, this is known as QALY (quality-adjusted life-year) maximization. This justification for QALY maximization may not hold, though, as it is difficult to reallocate health. Therefore, the allocation of health care should be seen as a matter of distributive justice as well as efficiency. A discrete choice experiment was undertaken to test consistency with the principles of QALY maximization and to quantify the willingness to trade life-year gains for distributive justice. An empirical ethics process was used to identify attributes that appeared relevant and ethically justified: patient age, severity (decomposed into initial quality and life expectancy), final health state, duration of benefit, and distributional concerns. Only 3% of respondents maximized QALYs with every choice, but scenarios with larger aggregate QALY gains were chosen more often and a majority of respondents maximized QALYs in a majority of their choices. However, respondents also appeared willing to prioritize smaller gains to preferred groups over larger gains to less preferred groups. Marginal analyses found a statistically significant preference for younger patients and a wider distribution of gains, as well as an aversion to patients with the shortest life expectancy or a poor final health state. These results support the existence of an equity-efficiency tradeoff and suggest that well-being could be enhanced by giving priority to programs that best satisfy societal preferences. Societal preferences could be incorporated through the use of explicit equity weights, although more research is required before such weights can be used in priority setting.


Dissecting KMT2D missense mutations in Kabuki syndrome patients.
Kabuki syndrome is a rare autosomal dominant condition characterized by facial features, various organs malformations, postnatal growth deficiency and intellectual disability. The discovery of frequent germline mutations in the histone methyltransferase KMT2D and the demethylase KDM6A revealed a causative role for histone modifiers in this disease. However, the role of missense mutations has remained unexplored. Here, we expanded the mutation spectrum of KMT2D and KDM6A in KS by identifying 37 new KMT2D sequence variants. Moreover, we functionally dissected 14 KMT2D missense variants, by investigating their impact on the protein enzymatic activity and the binding to members of the WRAD complex. We demonstrate impaired H3K4 methyltransferase activity in 9 of the 14 mutant alleles and show that this reduced activity is due in part to disruption of protein complex formation. These findings have relevant implications for diagnostic and counseling purposes in this disease.


World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics.
Prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20-30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention. The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy. We identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations. Currently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence. WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.


Study of aerobic granulocyte functional activity in the presence of a radiosensitizer (metronidazole).
The in vitro effects of metronidazole on the production of reactive oxygen species by polymorphonuclear (PMN) cells were studied by means of nitroblue tetrazolium and luminol-dependent chemiluminescence. At therapeutic doses of metronidazole (4.98-24.86 microg/mL) significant inhibition of the production of reactive oxygen species was noted in both methods. The inhibitory effect was in a dose-dependent pattern. The data suggest a scavenging mechanism of metronidazole on reactive oxygen species generated by PMN.


Chronic stress effects on memory: sex differences in performance and monoaminergic activity.
Increasing evidence suggests that the time course of advantageous versus deleterious effects of stress on physiologic function is also apparent in some brain functions, including learning and memory. This article reviews the effects of chronic stress on behavioral performance and, more importantly, shows that sex of the subject, as well as duration and intensity of stress, is an important determinant of the functional/behavioral, neurochemical, and anatomical consequences of the stress. Following chronic stress (7-28 days of restraint, 6 h/day), male and female rats were tested on a visual memory task (object recognition) and two spatial memory tasks (object placement and radial arm maze). At 21 days, stress impaired males on all tasks while females were either enhanced (spatial memory tasks) or not impaired (nonspatial memory tasks). Additionally, the influence of the hypothalamic-pituitary-adrenocortical axis in mediating the sex-specific responses to stress is considered. Behavioral and neurochemical assessments following chronic stress in ovariectomized females, with and without estradiol, suggest that estrogen exerts both organizational and activational influences on the observed sex differences in response to stress. Furthermore, stress differentially affected central transmitter levels in the frontal cortex, hippocampus, and amygdala depending on sex. The possible role of these sex-specific changes in neurotransmitter levels in mediating behavioral differences in response to stress is discussed. While these results are thus far limited to a few studies and require both further investigation and verification, chronic stress appears to be associated with distinct, sex-differentiated behavioral/cognitive and neurochemical responses. We conclude that sex differences must be taken into account when investigating or describing stress and associated sequalae.


Gene Expression and miRNAs Profiling: Function and Regulation in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer.
Breast cancer is the second most common cause of cancer-related deaths among women worldwide. It is a heterogeneous disease with four major molecular subtypes. One of the subtypes, human epidermal growth factor receptor 2 (HER2)-enriched (HER2-positive) is characterized by the absence of estrogen and progesterone receptors and overexpression of HER2 receptor, and accounts for 15-20% of all breast cancers. Despite the anti-HER2 and cytotoxic chemotherapy, HER2 subtype is an aggressive disease with significant mortality. Recent advances in molecular biology techniques, including gene expression profiling, proteomics, and microRNA analysis, have been extensively used to explore the underlying mechanisms behind human breast carcinogenesis and metastasis including HER2-positive breast cancer, paving the way for developing new targeted therapies. This review focuses on recent advances on gene expression and miRNA status in HER2-positive breast cancer.


A collaborative strategy to improve geriatric medical education.
Age-related demographic change is not being matched by a growth in relevant undergraduate medical education, in particular communication skills pertinent to elderly patients. To address this, a workshop for medical students focusing on important communication skills techniques for interacting with patients with dementia was designed by clinicians from the Geriatric, General Practice and Psychiatry departments at the University of Oxford. One hundred and forty-four first-year clinical students (Year 4 of the 6-year course; Year 2 of the 4-year graduate-entry course) attended the teaching. One hundred and twenty-nine students returned feedback forms with 104 forms matched for individual performance before and after the session. Feedback forms assessed student-perceived confidence in communicating with patients with dementia before and after the session using a 4-point Likert scale with corresponding numerical value (low (1), medium (2), high (3), very high (4)). Using the Wilcoxon Signed-Rank Test on the 104 matched forms, student-perceived confidence was higher post-teaching intervention (median = 2.75) than pre-intervention (median = 1.50). This difference was statistically significant with large effect size, Z = -8.47, P < 0.001, r = -0.59. Free-text comments focused on non-verbal communication skills teaching, suggesting that these sessions were most beneficial for topics hardest to teach in lecture-based approaches. The teaching aimed to promote patient-centred care and multidisciplinary collaborative practice, encourage student self-reflection and peer-assisted education and provide insight into the needs of patients with dementia. Student feedback indicated that these objectives had been met. This easily replicable teaching method provides a simple means of improving communication skills.


Aerococcus urinae: A Rare Cause of Endocarditis Presenting With Acute Stroke.
Aerococcus urinae is a rare organism infrequently isolated from cultures. Mostly known to cause urinary tract infection, it can cause bacteremia leading to severe urosepsis and infective endocarditis. Embolization is frequently reported with Aerococcus urinae endocarditis (AUE); hence, the presentation is highly variable. Sequelae such as various central nervous system manifestations, sepsis, valvular regurgitation with heart failure and even coronary artery involvement have been reported. We report a case of a 58-year-old man with AUE of the aortic valve, severe aortic regurgitation and embolic stroke as a result of embolization from AUE and ultimately required aortic valve replacement. Our case highlights this rare cause of endocarditis and offers insight into the variability of patient presentation and risk factors to consider.


Cervical myelopathy associated with intracranial dural arteriovenous fistula: MR findings before and after treatment.
The MR findings in three patients with intracranial dural arteriovenous fistula associated with cervical myelopathy are described. The MR appearance of an enlarged cord with associated abnormal signal and enhancement is nonspecific and can simulate tumor, demyelination, and inflammation. Enlarged perimedullary vessels may not always be identifiable, but if present, should suggest the presence of an arteriovenous fistula.


Patency of saphenous vein coronary artery bypass grafts from the vascular prosthesis of the ascending aorta.
Patients who have Stanford type A aortic dissection with impaired coronary arteries or who have aneurysms from the ascending aorta to the aortic arch with coronary artery disease need coronary artery bypass grafting (CABG) with tube graft replacement of the ascending aorta simultaneously. When vein grafts are used for CABG in these patients, the proximal anastomoses of vein grafts are attached to the prosthetic tube graft of the ascending aorta. However, the validity of proximal anastomoses of vein grafts to the prosthetic tube graft of the ascending aorta has not been confirmed. We retrospectively analyzed patients who underwent venous coronary bypass grafting with prosthetic graft replacement of the ascending aorta. Between January 1984 and October 2002, 35 patients underwent CABG using saphenous vein grafts at the time of tube graft replacement of the ascending aorta, and the proximal anastomoses of the vein grafts were attached to the tube graft of the ascending aorta. Thirty-three venous bypass grafts were analyzed in 24 survivors. The postoperative catheterization showed only one early vein graft occlusion of 16 vein grafts anastomosed distally to the left anterior descending artery (LAD). All 14 venous grafts anastomosed to the right coronary artery (RCA) and 3 to the left circumflex artery (LCX) were patent. Therefore, the postoperative patency rate at discharge was 97.0% (32/33). Spiral computed tomography performed for long term follow-up revealed occlusion of two vein grafts (3.5 years and 9.7 years) anastomosed to the LAD. The patency rate of vein grafts anastomosed from prosthetic grafts of the ascending aorta to the native coronary arteries was similar to that of conventional CABG using saphenous vein grafts.


Late deaths after treatment for childhood cancer.
An investigation of 749 deaths occurring among 4082 patients surviving at least five years after the diagnosis of childhood cancer in Britain before 1971 has been undertaken. Of the 738 with sufficient information the numbers of deaths attributable to the following causes were: recurrent tumour, 550 (74%), a second primary tumour, 61 (8%), a medical condition related to treatment of the tumour, 49 (7%), an traumatic death unrelated to the tumour or its treatment, 34 (5%), finally, any other cause unrelated to the tumour or its treatment, 44 (6%). Less than 10% of five year survivors of non-Hodgkin lymphomas, neuroblastoma, retinoblastoma, Wilms' tumour, or a soft tissue sarcoma died of recurrent tumour during the next 15 years, while more than 25% of five year survivors of Hodgkin's disease, ependymoma, medulloblastoma, and Ewing's tumour died of recurrent tumour during the corresponding period. Almost 50% of five year survivors of acute lymphoblastic leukaemia died of recurrent disease during the corresponding 15 years, a large proportion of deaths being due to central nervous system relapse in an era before central nervous system prophylaxis was routinely given. Comparison of the mortality observed with that expected from mortality rates in the general population indicated three times the expected number of deaths from non-neoplastic causes. Five times the expected number of deaths from cardiovascular causes were observed, these were predominantly myocardial infarction and cerebrovascular accidents. There was no evidence of an excess in the number of suicides observed, but there were three times the expected number of deaths from accidents observed after central nervous system tumours. Two groups of patients were identified whose deaths were potentially avoidable. Seven patients with craniopharyngioma and panhypopituitarism presented with addisonian crises during periods of stress not adequately covered by exogenous corticosteroids. In the other group were children who received radiotherapy and later developed problems related to radiation fibrosis. We emphasize that our investigation relates to patients diagnosed with childhood cancer before 1971. The pattern of mortality that will emerge after recent treatment regimens, in which chemotherapy is being used more extensively, is likely to be different from that observed in our study.


Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations.
In Europe, neuropsychiatric diseases currently make up approximately a third of the total burden of disease. In 2004, 27% of the overall population was affected by at least one of the most frequent neuropsychiatric diseases such as Alzheimer's dementia, Parkinson's disease, stroke or depression. The annual costs of care exceed those of cancer, cardiovascular conditions and diabetes. In order to delay the onset or course of neurodegenerative diseases, the available potential should be utilized. As well as improving quality of life of patients and relatives, this may reduce the great financial burden caused by neurodegenerative disorders. However, the availability of established drugs or therapeutic agents is very limited. This paper reviews the state of current knowledge as to how homocysteine metabolism is relevant for neurodegenerative and other neuropsychiatric diseases, with particular emphasis on the evidence for prophylactic and therapeutic strategies. In the European countries, many people do not take the recommended daily minimum amount of folate and vitamin B12. Deficiency of these vitamins and secondary changes in the concentrations of associated metabolites, such as methylmalonic acid and homocysteine, may contribute to the onset and progression of neuropsychiatric diseases. This paper reviews the evidence regarding whether substitution of folate and vitamin B12 is beneficial, for example, in cerebrovascular disease, dementia and depression.


Sparse distributed representation of odors in a large-scale olfactory bulb circuit.
In the olfactory bulb, lateral inhibition mediated by granule cells has been suggested to modulate the timing of mitral cell firing, thereby shaping the representation of input odorants. Current experimental techniques, however, do not enable a clear study of how the mitral-granule cell network sculpts odor inputs to represent odor information spatially and temporally. To address this critical step in the neural basis of odor recognition, we built a biophysical network model of mitral and granule cells, corresponding to 1/100th of the real system in the rat, and used direct experimental imaging data of glomeruli activated by various odors. The model allows the systematic investigation and generation of testable hypotheses of the functional mechanisms underlying odor representation in the olfactory bulb circuit. Specifically, we demonstrate that lateral inhibition emerges within the olfactory bulb network through recurrent dendrodendritic synapses when constrained by a range of balanced excitatory and inhibitory conductances. We find that the spatio-temporal dynamics of lateral inhibition plays a critical role in building the glomerular-related cell clusters observed in experiments, through the modulation of synaptic weights during odor training. Lateral inhibition also mediates the development of sparse and synchronized spiking patterns of mitral cells related to odor inputs within the network, with the frequency of these synchronized spiking patterns also modulated by the sniff cycle.


Effects of nurse navigators on health outcomes of cancer patients.
Care coordination has received increased attention in recent years because it critically affects patient safety and care quality across services and settings. The effectiveness of systematically developed nurse navigator interventions for newly diagnosed cancer patients was evaluated. Seventy-eight patients participated in a nonequivalent control group pretest-posttest design study. The study design spanned a 3-month period for all participants. Patient outcome measures included quality of life, satisfaction with care, and length of hospital stay. Participants in the experimental program reported significant increases in several components of quality of life and with satisfaction with care and experienced fewer hospital stay days compared with the control group. This study provides evidence that standardized nurse navigator programs can improve patient outcomes in cancer care. Positive outcomes of the reduced length of stay and improved quality of life and patient satisfaction may help transform the cancer care delivery model toward more nurse-initiated cost-effective model.


Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarii.
This study characterized the effect of nucleus tractus solitarii (NTS) microinjection of the angiotensin II (Ang II) antagonist [Sar1, Thr8]Ang II on the baroreceptor control of heart rate in anesthetized rats. Reflex changes in heart rate were elicited by bolus intravenous injections of either phenylephrine or sodium nitroprusside before and after bilateral microinjection of [Sar1, Thr8]Ang II (100 pmol) or vehicle into the NTS. The slope of the relationship between the change in pulse interval and the change in mean arterial pressure was used as an index of baroreceptor reflex sensitivity. Bradycardia elicited by phenylephrine-induced increases in pressure was significantly greater after NTS injection of [Sar1, Thr8]Ang II. The slope of the pulse interval-arterial pressure relationship was 0.60 +/- 0.09 ms/mm Hg after injection, as compared with 0.42 +/- 0.07 ms/mm Hg before. In contrast, the baroreceptor reflex sensitivity index generated by decreases in pressure with nitroprusside was similar before and after injection. Vehicle injections did not alter the baroreceptor reflex index. Collectively, the data suggest that inhibition of endogenous Ang II in the NTS facilitates the baroreceptor reflex sensitivity to increases, but not decreases, in pressure. This new finding reveals the NTS as one site of action for the tonic effects of endogenous Ang II.


4-D micro-CT of the mouse heart.
Demonstrate noninvasive imaging methods for in vivo characterization of cardiac structure and function in mice using a micro-CT system that provides high photon fluence rate and integrated motion control. Simultaneous cardiac- and respiratory-gated micro-CT was performed in C57BL/6 mice during constant intravenous infusion of a conventional iodinated contrast agent (Isovue-370), and after a single intravenous injection of a blood pool contrast agent (Fenestra VC). Multiple phases of the cardiac cycle were reconstructed with contrast to noise and spatial resolution sufficient for quantitative assessment of cardiac function. Contrast enhancement with Isovue-370 increased over time with a maximum of approximately 500 HU (aorta) and 900 HU (kidney cortex). Fenestra VC provided more constant enhancement over 3 hr, with maximum enhancement of approximately 620 HU (aorta) and approximately 90 HU (kidney cortex). The maximum enhancement difference between blood and myocardium in the heart was approximately 250 HU for Isovue-370 and approximately 500 HU for Fenestra VC. In mice with Fenestra VC, volumetric measurements of the left ventricle were performed and cardiac function was estimated by ejection fraction, stroke volume, and cardiac output. Image quality with Fenestra VC was sufficient for morphological and functional studies required for a standardized method of cardiac phenotyping of the mouse.


Circulating Fatty Acid Synthase in pregnant women: Relationship to blood pressure, maternal metabolism and newborn parameters.
The enzyme FASN (fatty acid synthase) is potentially related with hypertension and metabolic dysfunction. FASN is highly expressed in the human placenta. We aimed to investigate the relationship circulating FASN has with blood pressure, maternal metabolism and newborn parameters in healthy pregnant women. Circulating FASN was assessed in 115 asymptomatic pregnant women in the second trimester of gestation along with C-peptide, fasting glucose and insulin, post-load glucose lipids, HMW-adiponectin and blood pressure (the latter was assessed in each trimester of gestation). At birth, newborns and placentas were weighed. FASN expression was also able to be assessed in 80 placentas. Higher circulating FASN was associated with lower systolic blood pressure (SBP), with a more favourable metabolic phenotype (lower fasting glucose and insulin, post load glucose, HbAc1, HOMA-IR and C-peptide), and with lower placental and birth weight (all p < 0.05 to p < 0.001). Placental FASN expression related positively to circulating FASN (p < 0.005) and negatively to placental weight (p < 0.05). Our observations suggest a physiological role of placental FASN in human pregnancy. Future studies will clarify whether circulating FASN of placental origin does actually regulate placental and fetal growth, and (thereby) has a favourable influence on the pregnant mother's insulin sensitivity and blood pressure.


Resource utilization and costs before and after total joint arthroplasty.
The purpose of this study was to compare pre- and post-surgical healthcare costs in commercially insured total joint arthroplasty (TJA) patients with osteoarthritis (OA) in the United States (U.S.). Using a large healthcare claims database, we identified patients over age 39 with hip or knee OA who underwent unilateral primary TJA (hip or knee) between 1/1/2006 and 9/30/2007. Utilization of healthcare services and costs were aggregated into three periods: 12 months "pre-surgery," 91 days "peri-operative," and 3 to 15 month "follow-up," Mean total pre-surgery costs were compared with follow-up costs using Wilcoxon signed-rank test. 14,912 patients met inclusion criteria for the study. The mean total number of outpatient visits declined from pre-surgery to follow-up (18.0 visits vs 17.1), while the percentage of patients hospitalized increased (from 7.5% to 9.8%) (both p < 0.01). Mean total costs during the follow-up period were 18% higher than during pre-surgery ($11,043 vs. $9,632, p < 0.01), largely due to an increase in the costs of inpatient care associated with hospital readmissions ($3,300 vs. $1,817, p < 0.01). Pharmacotherapy costs were similar for both periods ($2013 [follow-up] vs. $1922 [pre-surgery], p = 0.33); outpatient care costs were slightly lower in the follow-up period ($4338 vs. $4571, p < 0.01). Mean total costs for the peri-operative period were $36,553. Mean total utilization of outpatient healthcare services declined slightly in the first year following TJA (exclusive of the peri-operative period), while mean total healthcare costs increased during the same time period, largely due to increased costs associated with hospital readmissions. Further study is necessary to determine whether healthcare costs decrease in subsequent years.


Limits of the linear accumulation regime of DGT sensors.
A key question for the practical application of DGT (Diffusive Gradients in Thin films) as dynamic sensors in the environmental monitoring of trace metals is the influence of pH and dissolved ligands over the linear accumulation regime. Protons compete with metal ions for the binding to the DGT resin sites at relatively low pH, whereas high affinity dissolved ligands compete with resin sites for the binding of metals. Any of the two phenomena can lead to a departure from the linear accumulation regime and an underestimation of the actual species concentration in solution. These effects are studied here through numerical simulation of the diffusion-reaction processes in both gel and resin domains using a detailed chemical model of metal ions and protons interacting with resin sites. Results were tested successfully against experimental data of the Cd-NTA representative system. Charts to delimitate the range of experimental conditions (pH, ligand concentration and strength) where the linear accumulation regime prevails, can be helpful for designing sampling strategies in field conditions. For example, it is foreseen that perturbations of linear regime within 10 h of deployment are negligible above pH 5 and weak complexation (log K' < 0) or above pH 7 and strong complexation (log K' < 3), where K' is the effective stability constant. These plots can also be approximately used for partially labile systems whenever the time is replaced with the product lability degree times t.


When the Spirit Is Willing, but the Flesh Is Weak: Developmental Differences in Judgments About Inner Moral Conflict.
Sometimes it is easy to do the right thing. But often, people act morally only after overcoming competing immoral desires. How does learning about someone's inner moral conflict influence children's and adults' moral judgments about that person? Across four studies, we discovered a striking developmental difference: When the outcome is held constant, 3- to 8-year-old children judge someone who does the right thing without experiencing immoral desires to be morally superior to someone who does the right thing through overcoming conflicting desires-but adults have the opposite intuition. This developmental difference also occurs for judgments of immoral actors: Three- to 5-year-olds again prefer the person who is not conflicted, whereas older children and adults judge that someone who struggles with the decision is morally superior. Our findings suggest that children may begin with the view that inner moral conflict is inherently negative, but, with development, come to value the exercise of willpower and self-control.


Bond strength tests of dental adhesive systems and their correlation with clinical results - A meta-analysis.
To evaluate the variability of bond strength test results of adhesive systems (AS) and to correlate the results with clinical parameters of clinical studies investigating cervical restorations. Regarding the clinical studies, the internal database which had previously been used for a meta-analysis on cervical restorations was updated with clinical studies published between 2008 and 2012 by searching the PubMed and SCOPUS databases. PubMed and the International Association for Dental Research abstracts online were searched for laboratory studies on microtensile, macrotensile and macroshear bond strength tests. The inclusion criteria were (1) dentin, (2) testing of at least four adhesive systems, (3) same diameter of composite and (4) 24h of water storage prior to testing. The clinical outcome variables were retention loss, marginal discoloration, detectable margins, and a clinical index comprising the three parameters by weighing them. Linear mixed models which included a random study effect were calculated for both, the laboratory and the clinical studies. The variability was assessed by calculating a ratio of variances, dividing the variance among the estimated bonding effects obtained in the linear mixed models by the sum of all variance components estimated in these models. Thirty-two laboratory studies fulfilled the inclusion criteria comprising 183 experiments. Of those, 86 used the microtensile test evaluating 22 adhesive systems (AS). Twenty-seven used the macrotensile test with 17 AS, and 70 used the macroshear test with 24 AS. For 28 AS the results from clinical studies were available. Microtensile and macrotensile (Spearman rho=0.66, p=0.007) were moderately correlated and also microtensile and macroshear (Spearman rho=0.51, p=0.03) but not macroshear and macrotensile (Spearman rho=0.34, p=0.22). The effect of the adhesive system was significant for microtensile and macroshear (p < 0.001) but not for macrotensile. The effect of the adhesive system could explain 36% of the variability of the microtensile test, 27% of the macrotensile and 33% of the macroshear test. For the clinical trials, about 49% of the variability of retained restorations could be explained by the adhesive system. With respect to the correlation between bond strength tests and clinical parameters, only a moderate correlation between micro- and macrotensile test results and marginal discoloration was demonstrated. However, no correlation between these tests and a retention loss or marginal integrity was shown. The correlation improved when more studies were included compared to assessing only one study. The high variability of bond strength test results highlights the need to establish individual acceptance levels for a given test institute. The weak correlation of bond-strength test results with clinical parameters leads to the conclusion that one should not rely solely on bond strength tests to predict the clinical performance of an adhesive system but one should conduct other laboratory tests like tests on the marginal adaptation of fillings in extracted teeth and the retention loss of restorations in non-retentive cavities after artificial aging.


Racial/ancestral diversity in 174 toxicity-related radiogenomic studies: A systematic review.
This study systematically reviews the distribution of racial/ancestral features and their inclusion as covariates in genetic-toxicity association studies following radiation therapy. Original research studies associating genetic features and normal tissue complications following radiation therapy were identified from PubMed. The distribution of radiogenomic studies was determined by mining the statement of country of origin and racial/ancestrial distribution and the inclusion in analyses. Descriptive analyses were performed to determine the distribution of studies across races/ancestries, countries, and continents and the inclusion in analyses. Among 174 studies, only 23 with a population of more one race/ancestry which were predominantly conducted in the United States. Across the continents, most studies were performed in Europe (77 studies averaging at 30.6 patients/million population [pt/mil]), North America (46 studies, 20.8 pt/mil), Asia (46 studies, 2.4 pt/mil), South America (3 studies, 0.4 pt/mil), Oceania (2 studies, 2.1 pt/mil), and none from Africa. All 23 studies with more than one race/ancestry considered race/ancestry as a covariate, and three studies showed race/ancestry to be significantly associated with endpoints. Most toxicity-related radiogenomic studies involved a single race/ancestry. Individual Participant Data meta-analyses or multinational studies need to be encouraged.


SOCS1 inhibits tumor necrosis factor-induced activation of ASK1-JNK inflammatory signaling by mediating ASK1 degradation.
We have previously shown that ASK1 undergoes ubiquitination and degradation in resting endothelial cells (EC) and that proinflammatory cytokine tumor necrosis factor (TNF) induces deubiquitination and stabilization, leading to ASK1 activation. However, the mechanism for the regulation of ASK1 stability is not known. In the present study, we have shown that SOCS1, a member of suppressor of cytokine signaling, induces ASK1 degradation. SOCS1 was constitutively expressed in EC and formed a labile complex with ASK1 that can be stabilized by proteasomal inhibitors. The phosphotyrosine-binding SH2 domain of SOCS1 was critical for its association with ASK1. Thus a SOCS1 mutant defective in phosphotyrosine binding failed to bind to and induce ASK1 degradation. Phosphotyrosine of ASK1 was induced in response to growth factors, and TNF induced dephosphorylation and dissociation of ASK1 from SOCS1. ASK1 with a mutation at Tyr-718 diminished the binding to SOCS1, suggesting that the phosphotyrosine-718 of ASK1 is critical for SOCS1 binding. Moreover, ASK1 expression and activity were up-regulated in SOCS1-deficient mice and derived EC, resulting in enhanced TNF-induced activation of JNK, expression of proinflammatory molecules, and apoptotic responses. We concluded that SOCS1 functions as a negative regulator in TNF-induced inflammation in EC, in part, by inducing ASK1 degradation.


Pathology of superficial bladder cancer with emphasis on carcinoma in situ.
The coexistence of carcinoma in situ in flat epithelium adjacent to tumors is prognostically significant and is associated with an increased incidence of tumor recurrence and invasion. Recent investigations have been aimed at finding markers that will help identify flat areas of dysplasia or low-grade papillary transitional cell carcinomas that have a high potential to evolve into invasive tumors. Both DNA and karyotype analyses, as well as cell surface markers, have been examined in some detail and could have clinical value in certain settings. The tumor DNA index as measured by flow cytometry of nuclei retrieved from deparaffined sections may be particularly useful as a predictor of tumor recurrences and, possibly, tumor invasion as well. The diagnosis of superficial disease rests on urine cytology and the histopathologic assessment of tissue biopsies; however, intra- and inter-observer reproducibility of tissue and cytologic diagnoses by pathologists is a significant problem. The application of new technologies, such as flow cytometric analysis of deparaffined nuclei, may reduce the subjectivity involved in the light microscopic assessment of pathology specimens.


User-Centered Design and Evaluation of a Web-Based Decision Aid for Older Adults Living With Mild Cognitive Impairment and Their Health Care Providers: Mixed Methods Study.
Mild cognitive impairment (MCI) is often considered a transitional state between normal and pathologic (eg, dementia) cognitive aging. Although its prognosis varies largely, the diagnosis carries the risk of causing uncertainty and overtreatment of older adults with MCI who may never progress to dementia. Decision aids help people become better informed and more involved in decision making by providing evidence-based information about options and possible outcomes and by assisting them in clarifying their personal values in relation to the decision to be made. This study aimed to incorporate features that best support values clarification and adjust the level of detail of a web-based decision aid for individuals with MCI. We conducted a rapid review to identify options to maintain or improve cognitive functions in individuals with MCI. The evidence was structured into a novel web-based decision aid designed in collaboration with digital specialists and graphic designers. Qualitative and user-centered evaluations were used to draw on users' knowledge, clarify values, and inform potential adoption in routine clinical practice. We invited clinicians, older adults with MCI, and their caregivers to evaluate the decision aid in 6 consecutive rounds, with new participants in each round. Quantitative data were collected using the Values Clarity and Informed subscales of the Decisional Conflict Scale, the System Usability Scale, the Ottawa Acceptability questionnaire, and a 5-point satisfaction rating scale. We verified their comprehension using a teach-back method and recorded usability issues. We recorded the audio and computer screen during the session. An inductive thematic qualitative analysis approach was used to identify and describe the issues that arose. After each round, an expert panel met to prioritize and find solutions to mitigate the issues. An integrated analysis was conducted to confirm our choices. A total of 7 clinicians (social workers, nurses, family physicians, psychologists) and 12 older (≥60 years) community-dwelling individuals with MCI, half of them women, with education levels going from none to university diploma, were recruited and completed testing. The thematic analysis revealed 3 major issues. First, the user should be guided through the decision-making process by tailoring the presentation of options to users' priorities using the values clarification exercise. Second, its content should be simple, but not simplistic, notably by using information layering, plain language, and pictograms. Third, the interface should be intuitive and user friendly, utilize pop-up windows and information tips, avoid drop-down menus, and limit the need to scroll down. The quantitative assessments corroborated the qualitative findings. This project resulted in a promising web-based decision aid that can support decision making for MCI intervention, based on the personal values and preferences of the users. Further ongoing research will allow its implementation to be tested in clinical settings.


Alcohol use and wages: new results from the National Household Survey on Drug Abuse.
A recent study published in the Journal of Health Economics by French and Zarkin [French, M.T., Zarkin, G.A., 1995. Is moderate alcohol use related to wages? Evidence from four worksites, Journal of Health Economics 14, 319-344] found evidence of a positive, inverse-U-shaped relationship between wages and alcohol consumption for individuals at four worksites. In this paper, we attempted to replicate French and Zarkin's findings using a combined sample of prime-age workers from the 1991 and 1992 National Household Surveys on Drug Abuse (NHSDA). Whereas French and Zarkin found that individuals who consume approximately 1.5 to 2.5 drinks per day have higher wages than non-drinkers and heavy drinkers, we found no evidence of a turning point at this consumption level for either men or women. Our results do suggest that men who use alcohol have approximately 7% higher wages than men who do not drink, and this apparent wage premium is approximately the same over a wide range of alcohol consumption. For women, the estimated alcohol use premium is approximately half as large as for men and is statistically insignificant.